This application deals with the use of chromatography in commercial scale preparative separations. More particularly, our invention deals with the branch of simulated moving bed chromatography as applied to the separation of chiral substances from a racemic mixture. Our contribution to such separations which is the subject of this application arises from the recognition that operating at low values of k', the capacity factor, is quite beneficial in chiral separations even though classical liquid chromatography theory teaches operation at high values of k' as one prerequisite to successful separations. To better understand our invention in the context of theory and conventional practice it will be helpful to briefly review some of the relevant principles of liquid chromatography.
One fundamental property in liquid chromatography is k', the capacity factor, which is defined as ##EQU1## where n.sub.s is the total moles of material being separated in the stationary phase and n.sub.m is the number of moles in the mobile phase. Where there are several components present, the capacity factor for the ith component is ##EQU2## The retention time, t.sub.r, for component i, t.sub.r (i), is related to the time it takes for the mobile phase to travel the length of the column, t.sub.0, by the distribution of component between the stationary and mobile phases according to the equation, ##EQU3## Thus, the capacity factor k' also is related to the relative retention time of the component in question.
For two components, the ratio of their relative retention times, .alpha., is ##EQU4## where .alpha..sub.ij is the selectivity factor between components i and j. Finally, the volume, V.sub.r, of the mobile phase required to elute a component as measured to the apex of the peak is related to the flow rate, F, of the mobile phase and retention time of the component by, EQU V.sub.r (i)=t.sub.r (i)F
from which it follows that EQU V.sub.r (i)=V.sub.0 [1+k'(i)] (4) EQU [V.sub.r (i)-V.sub.0 ]/V.sub.O =k' (5)
and ##EQU5## Thus, classical liquid chromatography theory as supported by much experimental evidence leads to the conclusions that the retention volume of a particular component, relative to the retention volume of the pure mobile phase, depends only on the capacity factor for the component, although relative retention volumes and relative retention times for two components depend only on the ratio of the two capacity factors, and it is the ratio of the capacity factors which define selectivity.
One form of chromatography well adapted to continuous, commercial-size separation is simulated moving bed chromatography. In continuous moving bed chromatography the stationary phase moves relative to the feed and mobile phase inputs, and the extract and raffinate outputs. Because of the difficulty of implementing a moving stationary phase in chromatographic separations its simulation is favored in practice (hence the name simulated moving bed chromatography) where incremental positional changes of the input and output streams, relative to a static stationary phase, is effected at regular intervals. Although many of the foregoing relations apply to simulated moving bed chromatography some additional nuances are applicable when the separations are of chiral substances using conventional chiral stationary phases.
One important observation from the foregoing review of some salient theoretical aspects of liquid chromatography is the affect of k' on the retention time and retention volume, EQU k'=t.sub.r -t.sub.0 =V.sub.r -V.sub.0
Whereas one normally seeks to maximize the difference in retention time between a component and the mobile phase in order to increase the difference in retention time between two components, this requires a large k' which has the ancillary undesirable effect of increasing the retention volume of the mobile phase for the components. Thus, the accepted practice in analytical chromatography and in batch mode preparative chromatography of operating at a high k', usually in the range 1&lt;k'&lt;10, has as a necessary consequence the usage of a large volume of mobile phase.
We have found the conditions in simulated moving bed chromatography can be significantly modified from those required for analytical and batch mode preparative chromatography. In particular, the separation of enantiomers from their racemic mixture using a chiral stationary phase in simulated moving bed chromatography can be performed effectively at low values of k', thereby minimizing the amount of mobile phase which is needed. Specifically, chiral separations may be performed efficiently where k' is less than 1, and especially in the range 0.1&lt;k'&lt;1. Since an appreciable cost of the separation process is associated with the mobile phase and its recovery from the raffinate and extract streams, our process affords substantial cost savings accruing from a lower mobile phase inventory, lower utility costs in recovering the mobile phase, and other ancillary costs.
It needs to be mentioned that even though certain types of separation currently effected by simulated moving bed (SMB) processes operate at the equivalent of a low k' it is not obvious to extend this knowledge to chiral separations because the mechanism of adsorption is fundamentally different. Thus, the adsorbents used in traditional separations such as that of the xylene isomers are zeolites such as X faujasites that have a high ion exchange capacity. With zeolites, the primary mechanism for adsorption is electrostatic attraction. The heat of adsorption, which is a direct measure of strength of the bonding between the adsorbate and the surface, is high (typically ca. 20 kcal). Consequently, a "strong" desorbent is required in these systems. Frequently, the desorbent is similar in polarity to that of the feed component. For example, xylenes are desorbed with alkyl aromatics a=such as p-diethylbenzene or toluene and chlorinated aromatic feedstocks are typical desorbed with chlorinated aromatic solvents. The strong adsorbate/adsorbent interaction and the high binding energies require the use of a strong desorbent.
The stationary phases used in chiral separations consist of an organic moiety bonded to an underlying inert core support such as silica. The mechanism of adsorption is very different from that of zeolites in that weak van der Waals forces predominate. Frequently, the adsorbate partitions in the "liquid phase" which is defined by the organic coating and molecules of the mobile phase. The binding energies are less than 1 kcal and the mobile phases are typically weak. Consequently, manipulation of the mobile phase composition and the use of "strong mobile phases" is unexpected for the very weak intermolecular interactions encountered with racemic organic molecules which are the feedstocks separated according to this invention. We also shall see that solubility plays a more significant role in our invention than in prior SMB separations.